Stable Pharmaceutical Composition Comprising a Fixed Dose Combination of Fenofibrate and an Hmg-Coa Reductase Inhibitor

ABSTRACT

A pharmaceutical composition for oral administration comprising a fixed dose combination of a first solid pharmaceutical composition containing fenofibrate as the active substance and second solid pharmaceutical composition containing an HMG-CoA reductase inhibitor such as a statin as the active substance, wherein the first and the second pharmaceutical compositions are present in separate entities in a single solid dosage form. For example a multilayer tablet, a two-layer tablet, or capsules or sachets containing the active ingredients in separate granulates or beads, either granulate or bead optionally being coated with a protective coating or an entero-coating.

The invention relates to a stable pharmaceutical composition comprisingat least two active pharmaceutical ingredients, namely fenofibrate as afirst ingredient and an HMG CoA reductase inhibitor or a derivativethereof as a second ingredient. More specifically, the invention relatesto a single solid dosage form for oral administration comprising a solidfenofibrate composition and a solid HMG-CoA reductase inhibitorcomposition, preferably a statin composition, the active substancesbeing present in separate entities.

BACKGROUND OF THE INVENTION

Clinical guidelines indicate that not only fibrate therapy but also acombination therapy with e.g. fenofibrate and a statin should be themost effective means of cholesterol and lipid management. In fact,treatment with fenofibrate is often prescribed together with a statin asclinicians seem to prefer the use of e.g. fenofibrate due to itstriglyceride-lowering and HDL-C increasing effects while a statin isused for its positive effects on lowering LDL-C and raising HDL-C.However, at present, such a combination therapy can only be achieved bythe use of two separate products, i.e. the patient needs to take e.g.one fenofibrate tablet or capsule together with another tablet orcapsule containing a statin.

Fenofibrate is chemically named2-[4-(4-chlorobenzoyl]-2-methyl-propanoic acid, 1-methylethyl ester.Fenofibric acid produces reductions in total cholesterol (total-C),LDL-C, apo-lipoprotein B, total triglycerides, and triglyceride richlipoprotein (VLDL) in treated patients. In addition, treatment withfenofibrate results in increases in high density lipoprotein (HDL) andapo-lipoprotein apoAl and apo All. Fenofibrate acts as a potent lipidregulating agent offering unique and clinical advantages over existingproducts in the fibrate family of drug substances. Fenofibrate producessubstantial reduction in plasma triglyceride levels inhypertriglyceridemic patients and in plasma cholesterol and LDL-C inhypercholesterolemic and mixed dyslipidemic patients.

Statins are HMG CoA reductase inhibitors. Useful statins includelovastatin, fluvastatin, rosuvastatin, pravastatin, atorvastatin andsimvastatin.

WO 2005/034908 discloses a combination of fenofibrate and a statin in asingle dosage form.

However, certain statins are known to be susceptible to degradationand/or oxidation when subjected to unfavorable physical and/or chemicalconditions. Also, an optimized combination drug product may call fordifferent release profiles of each of the active substances.

Accordingly, there is an unmet need for providing a single dosage formcomprising a combination of fenofibrate and a statin, in which allactive pharmaceutical substances remain stable and wherein the activesubstances are provided in a formulation providing maximumbioavailability and/or maximum therapeutic or pharmacological response.

SUMMARY OF THE INVENTION

The inventors have found that a fixed dose drug combination productcomprising fenofibrate and an HMG-CoA reductase inhibitor canadvantageously be prepared as a single solid dosage form in such amanner that the two active drug substances are present in separateentities. Thus, the active substances are effectively prevented from anydrug-drug interaction; the active substances may independently of eachother be provided in different release forms, i.e. in the form ofimmediate release, delayed release or controlled release compositions;and the stability of the combination drug product can be maximized dueto the possibility of optimizing the formulations of each of the activesubstances with respect to physical and/or chemical conditions.

Accordingly, in a first aspect the invention relates to a pharmaceuticalcomposition for oral administration comprising a first solidpharmaceutical composition containing fenofibrate as the activesubstance and second solid pharmaceutical composition containing anHMG-CoA reductase inhibitor as the active substance, wherein the firstand the second pharmaceutical composition are present in separateentities in a single solid dosage form.

In a second aspect, the invention relates to a pharmaceuticalcomposition for the treatment of a subject suffering fromatherosclerosis, hyperlipidemia, and/or hypercholesterolemia.

In a third aspect, the invention relates to a method of manufacturingthe pharmaceutical composition of the invention in a solid oral dosageform, for example a multilayer tablet.

In a further aspect, the invention relates to a single solid dosage formcomprising the pharmaceutical composition of the invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the term “active substance”, “active pharmaceuticalsubstance”, “active ingredient” or “active pharmaceutical ingredient”means any component that is intended to furnish pharmacological activityor other direct effect in the diagnosis, cure, mitigation, treatment, orprevention of disease, or to affect the structure or any function of thebody of man or other animals. The term includes those components thatmay undergo chemical change in the manufacture of the drug product andare present in the drug product in a modified form intended to furnishthe specified activity or effect.

As used herein, the term “vehicle” means any solvent or carrier in apharmaceutical product that has no pharmacological role. For example,water is the vehicle for xylocaine and propylene glycol is the vehiclefor many antibiotics.

In the present context, the term “solid dispersion” denotes a drug oractive ingredient or substance dispersed on a particulate level in aninert vehicle, carrier, diluent or matrix in the solid state, i.e.usually a fine particulate dispersion.

In the present context, the term “solid solution” denotes a drug oractive ingredient or substance dissolved on a molecular level in aninert vehicle, carrier, diluent or matrix in the solid state.

As used herein, the term “analog” means a chemical compound that isstructurally similar to another.

The term “drug” means a compound intended for use in diagnosis, cure,mitigation, treatment, or prevention of disease in man or other animals.

In this context, the term “dosage form” means the form in which the drugis delivered to the patient. This could be parenteral, topical, tablet,oral (liquid or dissolved powder), suppository, inhalation, transdermal,etc.

As used herein, the term “bioavailability” denotes the degree means towhich a drug or other substance becomes available to the target tissueafter administration. In the present context, the term “suitablebioavailability” is intended to mean that administration of acomposition according to the invention will result in a bioavailabilitythat is improved compared to the bioavailability obtained afteradministration of the active substance(s) in a plain tablet; or thebioavailability is at least the same or improved compared to thebioavailability obtained after administration of a commerciallyavailable product containing the same active substance(s) in the sameamounts. In particular it is desired to obtain quicker and larger and/ormore complete uptake of the active compound, and thereby provide for areduction of the administered dosages or for a reduction in the numberof daily administrations. Further, pharmaceutical compositions of theinvention may also reduce or negate the need for food to be takessimultaneously with the dosage form (in particular relevant for one orthe active substances contained in a composition of the invention,namely fenofibrate) thereby allowing patients more freedom on when thedrug is taken.

In this context, the term “medicine” means a compound used to treatdisease, injury or pain. Medicine is designated “prophylactic,” i.e. theart of preserving health, and “therapeutic”, i.e. the art of restoringhealth.

In the present context, the terms “controlled release” and “modifiedrelease” are intended to be equivalent terms covering any type ofrelease of fenofibrate or statin from a composition of the inventionthat is appropriate to obtain a specific therapeutic or prophylacticresponse after administration to a subject. A person skilled in the artknows how controlled release/modified release differs from the releaseof plain tablets or capsules. The terms “release in a controlled manner”or “release in a modified manner” have the same meaning as stated above.The terms include slow release (that results in a lower C_(max) andlater t_(max), but the half-life remains unchanged), extended release(that results in a lower C_(max), later t_(max), but apparent half-lifeis longer); delayed release (that result in an unchanged C_(max), butlag time and, accordingly, t_(max) is delayed, and the half-life remainsunchanged) as well as pulsatile release, burst release, sustainedrelease, prolonged release, chrono-optimized release, fast release (toobtain an enhanced onset of action) etc. Included in the terms is alsoe.g. utilization of specific conditions within the body e.g., differentenzymes or pH changes in order to control the release of the drugsubstance.

In this context, the term “erosion” or “eroding” means a gradualbreakdown of the surface of a material or structure, for example of atablet or the coating of a tablet.

In a first aspect, the invention relates to pharmaceutical compositionfor oral administration comprising a first solid pharmaceuticalcomposition containing fenofibrate as the active substance and secondsolid pharmaceutical composition containing an HMG-CoA reductaseinhibitor as the active substance, wherein the first and the secondpharmaceutical composition are present in separate entities in a singlesolid dosage form. The HMG-CoA reductase inhibitor is a statin selectedfrom the group consisting of atorvastatin, lovastatin, pravastatin,simvastatin, rosuvastatin, fluvastatin and pitavastatin.

In a preferred embodiment, the first solid pharmaceutical compositionand/or the second solid pharmaceutical composition is in the form ofgranulate, granules, grains, beads or pellets, which are mixed andfilled into capsules or sachets or are compressed to tablets byconventional methods. The granulate, granules, grains, beads or pelletscontaining the statin are optionally entero-coated or coated with aprotective coating.

In another preferred embodiment, there is provided a tablet in which thefirst and second pharmaceutical compositions are present in at least twoseparate layers, i.e. a bi-layer or multilayer tablet. The layerscomprising the first and second pharmaceutical compositions may beseparated by an intermediate, inactive layer, for example a layercomprising one or more disintegrants.

In another aspect, the invention provides a method for preparing asingle solid dosage form comprising a first solid pharmaceuticalcomposition containing fenofibrate as the active substance and secondsolid pharmaceutical composition containing an HMG-CoA reductaseinhibitor as the active substance, the first and the secondpharmaceutical composition being present in separate entities, whichmethod comprising the steps of:

i) preparing the first solid pharmaceutical composition,ii) preparing the second solid pharmaceutical composition, andiii) compressing the first and second compositions into a multilayertablet, the first and second compositions being present in separatelayers.

The Active Drug Substances

A first drug or active substance of the dosage forms and pharmaceuticalcompositions of this invention is fenofibrate as described above or ananalog thereof. However, it should be understood that this inventionincludes dosage forms and compositions comprising a mixture of two,three or even four different fibrates and/or fibric acids. Examples ofother useful fibrates are bezafibrate, ciprofibrate, clinofibrate,clofibrate, etofylline, clofibrate, fenofibrate, gemfibrozil,pirifibrate, simfibrate and tocofibrate; particularly useful aregemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate andactive metabolites and analogues thereof including any relevant fibricacid such as fenofibric acid.

A second drug or active substance of the dosage forms and pharmaceuticalcompositions of this invention is an HMG-CoA reductase inhibitor or aderivative thereof, for example a statin selected from the groupconsisting of atorvastatin, fluvastatin, pravastatin, lovastatin,rosuvastatin and simvastatin and pharmaceutically acceptable saltsthereof. For example, simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenylester, [1S-[1(alpha),3(alpha),7(beta),8(beta)(2S*,4S*),-8a(beta)]]. Theempirical formula of simvastatin is C₂₅H₃₈O₅ and its molecular weight is418.57.

Simvastatin is a white to off-white, nonhygroscopic, crystalline powderthat is practically insoluble in water, and freely soluble inchloroform, methanol and ethanol. Elevated plasma levels of totalcholesterol (total-C), LDL-C, and apolipoprotein B (Apo B) promote humanatherosclerosis and are risk factors for developing cardiovasculardisease, while increased levels of high-density lipoprotein cholesterol(HDL-C) and its transport complex, Apo A-1, are associated withdecreased cardiovascular risk. High plasma triglycerides (TG) andcholesterol-enriched TG-rich lipoproteins, including very-low-densitylipoproteins (VLDL), intermediate-density lipoproteins (IDL), andremnants, can also promote atherosclerosis. Elevated plasma TG isfrequently found in a triad with low HDL-C and small LDL particles, aswell as in association with non-lipid metabolic risk factors for CHD. Assuch, total plasma TG has not consistently been shown to be anindependent risk factor for CHD. Furthermore, the independent effect ofraising HDL-C or lowering TG on the risk of coronary and cardiovascularmorbidity and mortality has not been determined. Simvastatin has beenshown to reduce both normal and elevated LDL-C concentrations. LDL isformed from very-low-density lipoprotein (VLDL) and is catabolizedpredominantly by the high-affinity LDL receptor. Simvastatin undergoesextensive first-pass extraction in the liver, its primary site ofaction, with subsequent excretion of drug equivalents in the bile. As aconsequence of extensive hepatic extraction of simvastatin (estimated tobe >60% in man), the availability of drug to the general circulation islow.

Atorvastatin is a synthetic lipid-lowering agent. Atorvastatin is aninhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an earlyand rate-limiting step in cholesterol biosynthesis. Atorvastatin isuseful for example as the calcium salt, i.e.[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, calcium salt (2:1) trihydrate. The molecular weight ofatorvastatin calcium is 1209.42. Atorvastatin calcium is a white tooff-white crystalline powder that is insoluble in aqueous solutions ofpH 4 and below. Atorvastatin calcium is very slightly soluble indistilled water, pH 7.4 phosphate buffer, and acetonitrile, slightlysoluble in ethanol, and freely soluble in methanol. However,atorvastatin is also useful as the magnesium salt. The atorvastatinsalts may be either in crystalline form or in amorphous form or in amixture of crystalline and amorphous form.

Atorvastatin is rapidly absorbed after oral administration; maximumplasma concentrations occur within 1 to 2 hours. Extent of absorptionincreases in proportion to atorvastatin dose. The absolutebioavailability of atorvastatin (parent drug) is approximately 14% andthe systemic availability of HMG-CoA reductase inhibitory activity isapproximately 30%. The low systemic availability is attributed topresystemic clearance in gastrointestinal mucosa and/or hepaticfirst-pass metabolism. Although food decreases the rate and extent ofdrug absorption by approximately 25% and 9%, respectively, as assessedby Cmax and AUC, LDL-C reduction is said to be similar whetheratorvastatin is given with or without food. Plasma atorvastatinconcentrations are lower (approximately 30% for Cmax and AUC) followingevening drug administration compared with morning. However, LDL-Creduction is said to be the same regardless of the time of day of drugadministration

Pharmaceutically Acceptable Excipients and Additives

In the present context the term “pharmaceutically acceptable excipient”is intended to denote any material, which is inert in the sense that itsubstantially does not have any therapeutic and/or prophylactic effectper se. Such excipients may be added with the purpose of making itpossible to obtain a pharmaceutical, cosmetic and/or foodstuffcomposition, which have acceptable technical properties. A particulatematerial or a solid dosage form according to the invention may containone or more pharmaceutically acceptable excipients.

Examples of suitable excipients for use in a composition or solid dosageform according to the invention include fillers, diluents,disintegrants, binders, stabilizers, lubricants etc. or mixturesthereof. As the composition or solid dosage form according to theinvention may be used for different purposes, the choice of excipientsis normally made taken such different uses into considerations. Otherpharmaceutically acceptable excipients for suitable use are e.g.acidifying agents, alkalizing agents, preservatives, antioxidants,buffering agents, chelating agents, coloring agents, complexing agents,emulsifying and/or solubilizing agents, flavors and perfumes,humectants, sweetening agents, wetting agents etc.

It is well-known that statins are pharmacologically active in thehydroxy acid form, whereas the corresponding lactone form may beconsidered a prodrug which may convert to the active hydroxy acid invivo.

The active ingredient atorvastatin is included in the pharmaceuticalcomposition as a salt of the pharmacologically active hydroxy acid form,preferably the hemi-calcium salt or the magnesium salt, in crystallineor amorphous form. In a preferred embodiment of the invention,atorvastatin is used in the crystalline magnesium salt form.

The atorvastatin hydroxy acid form—lactone form equilibrium andinterconversion kinetics is pH highly dependent. The acid-catalyzedreaction is reversible, whereas the base-catalyzed reaction ispractically irreversible: At pH>6, the equilibrium reaction is notdetectable and greatly favors the hydroxy acid form (Kearney et al.,Pharmaceutical Research, 1993, vol. 10, no. 10, p. 1461-65).

Accordingly, it is advisable to establish a near-neutral or basicmicroenvironment for atorvastatin in the pharmaceutical composition inorder to stabilize the equilibrium, i.e. avoid presence of the inactivelactone form, for example an microenvironment having a pH above about 5or even a pH above about 6.

It is known to incorporate a pharmaceutically acceptable inorganicalkalizing compound into a pharmaceutical composition comprisingatorvastatin as a stabilizer. Such inorganic alkalizing compounds aretypically conventional basic salts of metals or alkaline earth metals,for example calcium salts (calcium carbonate, calcium hydroxide, dicalcium phosphate, tri calcium phosphate), magnesium salts (magnesiumcarbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate,and aluminum magnesium hydroxide), lithium salts (lithium hydroxide),potassium salts (potassium hydroxide) and sodium salts (sodiumbicarbonate, sodium borate, sodium carbonate, sodium hydroxide).Conventionally, the basic inorganic salts of calcium, lithium ormagnesium are utilized in a weight ratio ranging between about 0.1 to 1and about 50 to 1 of salt compound to atorvastatin (i.e. the activeingredient). Typically, calcium carbonate is used in an amount of atleast 5% w/w of the pharmaceutical composition and even up to as much asabout 70% w/w, typically in a w/w ratio atorvastatin-calcium carbonateof between 1:1 and 4:1. Without being bound to this theory, it iscontemplated that it is necessary to use a high amount of calciumcarbonate due to the low water solubility of calcium carbonate, below0.1 mg/mL at neutral pH.

Other useful pharmaceutically acceptable inorganic compounds are forexample talc and bentonite.

However, a basic or near-neutral microenvironment for atorvastatin mayalso be established by incorporating one or more pharmaceuticallyacceptable organic alkalizing compounds into the pharmaceuticalcomposition. Useful organic compounds include amines, amides andammonium compounds. Specific examples are ammonia, ammonium lactate,ammonium bicarbonate, ammonium hydroxide, ammonium phosphate dibasic,mono ethanolamine, di ethanolamine, tri ethanolamine, trihydroxymethylaminomethane, ethylenediamine, N-methyl glucamide,6N-methyl glucamine, meglucamine and L-lysine. A preferred compound istrometamol (IUPAC name: 2-amino-2-(hydroxymethyl)-1,3-propanediol; alsoknown as tris buffer, tham, tromethamine, trisaminol or trisamine).Trometamol is useful in an amount of below 10% w/w of the pharmaceuticalcomposition, preferably below 5% w/w. Typically, trometamol is used inthe pharmaceutical composition comprising atorvastatin in an amount ofat the most about 1% w/w of the composition. In a preferred embodimentof the invention, trometamol is used in an amount of below 1% w/w of theinvention, preferably below 0.8% W/w, more preferably below 0.7% w/w,even more preferably below about 0.6% w/w, such as about 0.5% w/w, ofthe composition.

Examples of suitable fillers, diluents and/or binders include lactose(e.g. spray-dried lactose, a-lactose, b-lactose, Tabletose®, variousgrades of Pharmatose®, Microtose® or Fast-Floc®), microcrystallinecellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® orSolka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (lowsubstituted), hydroxypropyl methylcellulose (HPMC) (e.g., Methocel E, Fand K, Metolose SH of Shin-Etsu, Ltd, such as, e.g. the 4,000 cps gradesof Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F andMetolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K;and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH),methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C,Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodiumcarboxymethylcellulose, carboxymethylene,carboxymethylhydroxyethylcellulose and other cellulose derivatives,sucrose, agarose, sorbitol, mannitol (e.g. Pearlitol 50C), dextrins,maltodextrins, starches or modified starches (including potato starch,maize starch and rice starch), calcium phosphate (e.g., basic calciumphosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate),calcium sulfate, calcium carbonate, sodium alginate, collagen etc.

Specific examples of diluents are e.g., calcium carbonate, dibasiccalcium phosphate, tribasic calcium phosphate, calcium sulfate,microcrystalline cellulose, powdered cellulose, dextrans, dextrin,dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch,pregelatinized starch, sucrose, sugar etc.

Specific examples of disintegrants are e.g. alginic acid or alginates,microcrystalline cellulose, hydroxypropyl cellulose and other cellulosederivatives, croscarmellose sodium (Ac-di-sol), crospovidone,polacrillin potassium, sodium starch glycolate, starch, pregelatinizedstarch, carboxymethyl starch (e.g. Primogel® and Explotab®) etc.

Specific examples of binders are e.g., acacia, alginic acid, agar,calcium carrageenan, sodium carboxymethylcellulose, microcrystallinecellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum,hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone,pregelatinized starch etc.

Glidants and lubricants may also be included in the first or,preferably, the second (statin-containing) composition. Examples includestearic acid, magnesium stearate, calcium stearate or other metallicstearate, talc, waxes and glycerides, light mineral oil, PEG, glycerylbehenate, colloidal silica, hydrogenated vegetable oils, corn starch,sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodiumbenzoate, sodium acetate etc.

Other excipients which may be included in a composition or solid dosageform of the invention are e.g., flavoring agents, coloring agents,taste-masking agents, pH-adjusting agents, buffering agents,preservatives, stabilizing agents, anti-oxidants, wetting agents,humidity-adjusting agents, surface-active agents (e.g. Polysorbate80/Tween 80), suspending agents, absorption enhancing agents, agents formodified release etc.

Other additives in a composition or a solid dosage form according to theinvention may be antioxidants like e.g. ascorbic acid, ascorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene, citricacid, hypophosphorous acid, monothioglycerol, potassium metabisulfite,propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite,sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate,tocopherol hemisuccinate, TPGS or other tocopherol derivatives, etc. Theconcentration of antioxidants in the carrier composition is normallyfrom about 0.1% w/w to about 5% w/w.

A composition or solid dosage form according to the invention may alsoinclude one or more surfactants or substances having surface-activeproperties. It is contemplated that such substances are involved in thewetting of the slightly soluble active substance and thus, contributesto improved solubility characteristics of the active substance. Suitablesurfactants for use in a composition or a solid dosage form according tothe invention are surfactants such as, e.g., hydrophobic and/orhydrophilic surfactants as those disclosed in WO 00/50007 in the name ofLipocine, Inc.

Specific examples of suitable surfactants are polyethoxylated fattyacids such as, e.g., fatty acid mono- or diesters of polyethylene glycolor mixtures thereof such as, e.g., mono- or diesters of polyethyleneglycol with lauric acid, oleic acid, stearic acid, myristic acid,ricinoleic acid, and the polyethylene glycol may be selected from PEG 4,PEG 5, PEG 6, PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20, PEG25, PEG 30, PEG 32, PEG 40, PEG 45, PEG 50, PEG 55, PEG 100, PEG 200,PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 10,000, PEG15,000, PEG 20,000, PEG 35,000, polyethylene glycol glycerol fatty acidesters, i.e. esters like the above-mentioned but in the form of glycerylesters of the individual fatty acids; glycerol, propylene glycol,ethylene glycol, PEG or sorbitol esters with e.g., vegetable oils likee.g., hydrogenated castor oil, almond oil, palm kernel oil, castor oil,apricot kernel oil, olive oil, peanut oil, hydrogenated palm kernel oiland the like, polyglycerized fatty acids like e.g., polyglycerolstearate, polyglycerol oleate, polyglycerol ricinoleate, polyglycerollinoleate, propylene glycol fatty acid esters such as, e.g., propyleneglycol monolaurate, propylene glycol ricinoleate and the like, mono- anddiglycerides like e.g. glyceryl monooleate, glyceryl dioleae, glycerylmono- and/or dioleate, glyceryl caprylate, glyceryl caprate etc.; steroland sterol derivatives; polyethylene glycol sorbitan fatty acid esters(PEG-sorbitan fatty acid esters) such as esters of PEG with the variousmolecular weights indicated above, and the various Tween® series (fromICI America, Inc.); polyethylene glycol alkyl ethers such as, e.g., PEGoleyl ether and PEG lauryl ether; sugar esters like e.g. sucrosemonopalmitate and sucrose monolaurate; polyethylene glycol alkyl phenolslike e.g. the Triton® X or N series (Union Carbide Chemicals & PlasticsTechnology Corporation); polyoxyethylene-polyoxypropylene blockcopolymers such as, e.g., the Pluronic® series from BASFAktiengesellschaft, the Synperonic® series from ICI America, Inc.,Emkalyx, Lutrol® from BASF Aktiengesellschaft, Supronic etc. The genericterm for these polymers is “poloxamers” and relevant examples in thepresent context are Poloxamer 105, 108, 122, 123, 124, 181, 182, 183,184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288,331, 333, 334, 335, 338, 401, 402, 403 and 407; sorbitan fatty acidesters like the Span® series (from ICI) or Arlacel® series (from ICI)such as, e.g., sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonooleate, sorbitan monostearate etc.; lower alcohol fatty acid esterslike e.g., oleate, isopropyl myristate, isopropyl palmitate etc.; ionicsurfactants including cationic, anionic and zwitterionic surfactantssuch as, e.g., fatty acid salts, bile salts, phospholipids, phosphoricacid esters, carboxylates, sulfates and sulfonates etc.

When a surfactant or a mixture of surfactants is present in acomposition or a solid dosage form of the invention, the concentrationof the surfactant(s) is normally in a range of from about 0.1-80% w/wsuch as, e.g., from about 0.1 to about 20% w/w, from about 0.1 to about15% w/w, from about 0.5 to about 10% w/w, or alternatively, from about0.10 to about 80% w/w such as, e.g. from about 10 to about 70% w/w, fromabout 20 to about 60% w/w or from about 30 to about 50% w/w.

In a specific aspect of the invention, the at least one of the one ormore pharmaceutically acceptable excipient is selected from the groupconsisting of silica acid or a derivative or salt thereof includingsilicates, silicon dioxide and polymers thereof; magnesiumaluminosilicate and/or magnesium aluminometasilicate, bentonite, kaolin,magnesium trisilicate, montmorillonite and/or saponite.

Solid Dosage Form Design Method of Manufacture

The first solid composition of the invention may be prepared by anymethod suitable for incorporation of poorly water-soluble activesubstances. The pharmaceutical compositions may be prepared by anyconvenient method such as, e.g. granulation, mixing, spray drying etc. Aparticularly useful method is the method disclosed in Applicants'co-pending international application published as WO 03/004001, whichdescribes a process for preparation of particulate material by acontrolled agglomeration method, i.e. a method, which enables acontrolled growth in particle size. The method involves spraying a firstcomposition comprising the active substance and a vehicle in liquid formonto a solid carrier. Normally, the vehicle has a melting point of atleast 5° C., but the melting point must indeed be below the meltingpoint of the active substance. In the present invention, the meltingpoint of the vehicle and should not exceed 250° C.

It is within the skills of the average practitioner to select a suitablevehicle being pharmaceutical acceptable, capable of dispersing or fullyor at least partly dissolving the active substance and having a meltingpoint in the desired range using general knowledge and routineexperimentation. Suitable candidate for carriers are described in WO03/004001, which is herein incorporated by reference.

In the present context, suitable vehicles are e.g., those mentioned asvehicles or as oily materials as well as those disclosed in WO03/004001. An advantage of using the controlled agglomeration methoddescribed in WO 03/004001 is that it is possible to apply a relativelylarge amount of a liquid system to a particulate material without havingan undesirable growth in particle size. Accordingly, in one embodimentof the invention, the particulate material of a pharmaceuticalcomposition has a geometric weight mean diameter dgw of 210 mm such as,e.g. 220 mm, from about 20 to about 2000, from about 30 to about 2000,from about 50 to about 2000, from about 60 to about 2000, from about 75to about 2000 such as, e.g. from about 100 to about 1500 mm, from about100 to about 1000 mm or from about 100 to about 700 mm, or at the mostabout 400 mm or at the most 300 mm such as, e.g., from about 50 to about400 mm such as, e.g., from about 50 to about 350 mm, from about 50 toabout 300 mm, from about 50 to about 250 mm or from about 100 to about300 mm.

The first compositions of the invention are preferably formed by spraydrying techniques, controlled agglomeration, freeze-drying or coating oncarrier particles or any other solvent removal process. The driedproduct contains the active substance present preferably in dissolvedform either fully dissolved as a solid solution or partly dissolved as asolid dispersion including a molecular dispersion and a solid solution.

The first composition of the invention may preferably be manufacturedusing a method comprising the steps of:

i) bringing the vehicle in liquid form, i.e. melting the vehicle ifsolid at room temperature,ii) maintaining the liquid vehicle at a temperature below the meltingpoint of the fibrate,iii) dissolving the desired amount of fibrate in the vehicle,iv) spraying the resulting solution onto a solid carrier having atemperature below the melting point of the vehicle,v) mechanically working the resulting composition to obtain particles,i.e. a particulate material, andvi) optionally subjecting the particulate material to conventionalmethods for preparing solid dosage forms.

In an important embodiment of the invention, at least part of thefibrate is present in the composition in the form of a solid dispersionincluding a molecular dispersion and a solid solution. Normally, about10% or more such as, e.g., about 20% or more, about 30% or more, about40% or more, about 50% or more, about 60% or more, about 70% or more,about 80% or more, about 90% or more such as, e.g., about 95% or more orabout 100% w/w of the fibrate is present in the vehicle in the form of asolid dispersion, provided that at least about 80% w/w of the totalamount of active substances is dissolved in the vehicle.

The first (fibrate-containing) composition may also be prepared using adispersion of micronized fenofibrate, i.e. crystalline fenofibratesubjected to micronizing, for example in a conventional jet mill, inorder to obtain a reduced crystalline particle size in the micron-range.Fenofibrate particles in the nano-range are also useful in the presentinvention.

A solid dispersion may be obtained in different ways e.g., by employingorganic solvents or by dispersing or dissolving the active substance inanother suitable medium (e.g. an oily material that is in liquid form atroom temperature or at elevated temperatures). Solid dispersions(solvent method) are prepared by dissolving a physical mixture of theactive substance (e.g. a drug substance) and the carrier in a commonorganic solvent, followed by evaporation of the solvent. The carrier isoften a hydrophilic polymer. Suitable organic solvents includepharmaceutical acceptable solvent in which the active substance issoluble such as methanol, ethanol, methylene chloride, chloroform,ethylacetate, acetone or mixtures thereof.

The second solid (statin-containing) composition may be prepared byconventional wet granulation techniques as disclosed in the Examplesbelow.

Suitable water-soluble carriers include polymers such as polyethyleneglycol, poloxamers, polyoxyethylene stearates,poly-epsilon-caprolactone, polyvinylpyrrolidone (PVP),polyvinylpyrrolidone-polyvinylacetate copolymer PVP-PVA (Kollidon VA64),polymethacrylic polymers (Eudragit RS, Eudragit RL, Eudragit NE,Eudragit E) and polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), methyl cellulose, andpoly(ethylene oxide) (PEO).

Polymers containing acidic functional groups may be suitable for soliddispersions, which release the active substance in a preferred pH rangeproviding acceptable absorption in the intestines. Such polymers may beone or more selected from the group comprising hydroxypropylmethylcellulose phtalate (HMPCP), polyvinyl acetate phthalate (PVAP),hydroxypropylmethylcellulose acetate succinate (HPMCAS), alginate,carbomer, carboxymethylcellulose, methacrylic acid copolymer (EudragitL, Eudragit S), shellac, cellulose acetate phthalate (CAP), starchglycolate, polacrylin, methyl cellulose acetate phthalate,hydroxypropylcellulose acetate phthalate, cellulose acetateterephthalate, cellulose acetate isophthalate and cellulose acetatetrimellitate.

The weight ratio of active substance to polymer may be in a range offrom about 3:1 to about 1:20. However, narrower ranges of from about 3:1to about 1:5, such as, e.g., from about 1:1 to about 1:3 or about mayalso be used.

Apart from using the organic solvent based method, solid dispersion orsolid solutions of one or more fibrates may be also obtained bydispersing and/or dissolving the active compound in the carriercomposition used in the controlled agglomeration method. Stabilizingagents etc. may be added in order to ensure the stability of the soliddispersion/solution.

Fenofibrate and a statin may be combined in the composition or soliddosage form of the invention by using the following method: Afenofibrate granulate is prepared as disclosed in WO 2005/034920 andexample 1 herein. A statin granulate is prepared using a conventionalwet granulation method. The two granulates are mixed and eithercompressed into tablets or filled into hard gelatine capsules orsachets. The statin granulate may be entero-coated or coated with aprotective coating, for example a film-forming polymer and stabilizers(antioxidants). The tablets might be sub-coated with a film-formingpolymer before coating with the statin suspension below.

Examples of film polymers include water soluble agents such ashydroxypropylmethylcellulose, Metolose® (HPMC),hydroxypropylmethylcellulose, Klucel® (HPC), polyvinyl alcohol (PVA),polyvinylpyrrolidone (PVP) or combinations of PVA and PVP (Kollicoat®IR) and acid soluble acrylic polymer (Eudragit E, soluble in gastricjuice).

Examples of antioxidants includes butylhydroxyanisol (BHA), ascorbylpalmitate, ascorbic acid or combinations of BHA, ascorbyl palmitate andcitric acid. Wetting and pH adjusting agent might be included in thecoating suspension Coating of the statin composition is performed inconventional coating equipment such as drum coater, perforated vessel orfluidized bed (Wurster insert).

Solid Dosage Forms

The pharmaceutical composition of the invention is prepared in a soliddosage form which may be a single unit dosage form or in the form of apolydepot dosage form containing a multiplicity of individual units suchas pellets, beads and/or granules.

Usually, the pharmaceutical composition in a solid dosage form of theinvention is intended for administration via the oral, buccal orsublingual administration route.

The invention also relates to the above-mentioned presentation form.Within the scope of the invention are compositions/solid dosage formsthat are intended to release the active substance in a fast release, adelayed release or modified release manner.

A useful solid dosage form comprises a pharmaceutical composition inparticulate form as described above. The details and particularsdisclosed under this main aspect of the invention apply mutatis mutandisto the other aspects of the invention. Accordingly, the properties withrespect to increase in bioavailability, therapeutic and/orpharmacological response, changes in bioavailability parameters,reduction in adverse food effect as well as release of one or morefibrates etc. described and/or claimed herein for pharmaceuticalcompositions in particulate form are analogues for a solid dosage formaccording to the present invention.

The solid dosage form, i.e. in unit dosage form, comprises from about100 to about 170 mg of fenofibrate, for example 100 mg or 110 mg or 120mg or 130 mg or 145 mg or 160 mg of fenofibrate, and from about 5 toabout 80 mg of statin or a pharmaceutically acceptable salt thereof, forexample 5 mg or 10 mg or 20 mg or 40 mg or 80 mg of simvastatin or ofatorvastatin.

In a preferred embodiment of the invention there is provided apharmaceutical composition, in a single solid dosage form, comprising afixed dose combination selected from the group consisting ofatorvastatin 5 mg and fenofibrate 100 mg; atorvastatin 10 mg andfenofibrate 100 mg; atorvastatin 20 mg and fenofibrate 100 mg;atorvastatin 40 mg and fenofibrate 100 mg; atorvastatin 80 mg andfenofibrate 100 mg; atorvastatin 5 mg and fenofibrate 110 mg;atorvastatin 10 mg and fenofibrate 110 mg; atorvastatin 20 mg andfenofibrate 110 mg; atorvastatin 40 mg and fenofibrate 110 mg;atorvastatin 80 mg and fenofibrate 110 mg; atorvastatin 5 mg andfenofibrate 120 mg; atorvastatin 10 mg and fenofibrate 120 mg:atorvastatin 20 mg and fenofibrate 120 mg; atorvastatin 40 mg andfenofibrate 120 mg; and atorvastatin 80 mg and fenofibrate 120 mg;atorvastatin 5 mg and fenofibrate 130 mg; atorvastatin 10 mg andfenofibrate 130 mg: atorvastatin 20 mg and fenofibrate 130 mg;atorvastatin 40 mg and fenofibrate 130 mg; and atorvastatin 80 mg andfenofibrate 130 mg; atorvastatin 5 mg and fenofibrate 145 mg;atorvastatin 10 mg and fenofibrate 145 mg: atorvastatin 20 mg andfenofibrate 145 mg; atorvastatin 40 mg and fenofibrate 145 mg; andatorvastatin 80 mg and fenofibrate 145 mg.

In another preferred embodiment there is provided a pharmaceuticalcomposition comprising, in a single solid dosage form, a fixed dosecombination selected from the group consisting of simvastatin 5 mg andfenofibrate 100 mg; simvastatin 10 mg and fenofibrate 100 mg;simvastatin 20 mg and fenofibrate 100 mg; simvastatin 40 mg andfenofibrate 100 mg; simvastatin 80 mg and fenofibrate 100 mg;simvastatin 5 mg and fenofibrate 110 mg; simvastatin 10 mg andfenofibrate 110 mg; simvastatin 20 mg and fenofibrate 110 mg;simvastatin 40 mg and fenofibrate 110 mg; simvastatin 80 mg andfenofibrate 110 mg; simvastatin 5 mg and fenofibrate 120 mg; simvastatin10 mg and fenofibrate 120 mg: simvastatin 20 mg and fenofibrate 120 mg;simvastatin 40 mg and fenofibrate 120 mg; and simvastatin 80 mg andfenofibrate 120 mg; simvastatin 5 mg and fenofibrate 130 mg; simvastatin10 mg and fenofibrate 130 mg: simvastatin 20 mg and fenofibrate 130 mg;simvastatin 40 mg and fenofibrate 130 mg; simvastatin 80 mg andfenofibrate 130 mg; simvastatin 5 mg and fenofibrate 145 mg; simvastatin10 mg and fenofibrate 145 mg: simvastatin 20 mg and fenofibrate 145 mg;simvastatin 40 mg and fenofibrate 145 mg; and simvastatin 80 mg andfenofibrate 145 mg.

The solid dosage forms comprising the pharmaceutical composition of theinvention are very stable. For example, the fibrate is present in anamount of at least about 90%, or at least about 95%, or at least about100%, relative to the amount prior to storage, when assayed after 3months of storage at a temperature of about 40° C. and a relativehumidity of about 75%. Also, the physical stability is very high as canbe seen from the Examples below.

The solid dosage form according to the invention is obtained byprocessing the particulate material according to the invention by meansof techniques well-known to a person skilled in the art. Usually, thisinvolves further addition of one or more of the pharmaceuticallyacceptable excipients mentioned herein.

The composition or solid dosage form according to the invention may bedesigned to release fenofibrate and/or simvastatin/atorvastatin in anysuitable manner provided that the increase in bioavailability ismaintained. Thus, the active substance(s) may be released relativelyfast in order to obtain an enhanced on-set of action, it may be releasedso as to follow zero or first order kinetics or it may be released in acontrolled or modified manner in order to obtain a predetermined patternof release. Plain formulations are also within the scope of the presentinvention.

The composition or solid dosage form according to the invention may alsobe coated with a film coating, an enteric coating, a modified releasecoating, a protective coating, an anti-adhesive coating etc.

A solid dosage form according to the invention may also be coated inorder to obtain suitable properties e.g. with respect to release of theactive substance. The coating may be applied on single unit dosage forms(e.g. tablets, capsules) or it may be applied on a polydepot dosage formor on its individual units.

Suitable coating materials are e.g. methylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic polymers,ethylcellulose, cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate, polyvinylalcohol,sodium carboxymethylcellulose, cellulose acetate, cellulose acetatephthalate, gelatin, methacrylic acid copolymer, polyethylene glycol,shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax,zein.

Plasticizers and other ingredients may be added in the coating material.The same or different active substance may also be added in the coatingmaterial. The pharmaceutical composition or a solid dosage formaccording to the invention is designed to release the fibrate in asuitable manner.

Other Aspects of the Invention

A pharmaceutical composition or a solid dosage form according to theinvention is designed to release the fibrate in a suitable manner.Specific release patterns as well as specific absorption patterns arementioned below.

In specific embodiments, the fibrate and/or the statin is released fromthe composition within about 2 hours such as, e.g., within about 1.5hours or within about 1 hour after oral administration, and/or about 50%w/w or more of the fibrate and/or the statin is released from thecomposition within about 30 min after oral administration, and/or about50% w/w or more of the fibrate and/or the statin is released from thecomposition within about 20 min after oral administration, and/or about60% w/w or more of the fibrate is released from the composition withinabout 1.5 hours after oral administration, and/or about 60% w/w or moreof the fibrate and/or the statin is released from the composition withinabout 1 hour after oral administration, and/or about 70% w/w or more ofthe fibrate and/or the statin is released from the composition withinabout 1.5 hours after oral administration, and/or about 70% W/W or moreof the fibrate and/or the statin is released from the composition withinabout 1 hour after oral administration, and/or about 85% w/w or more ofthe fibrate and/or the statin is released from the composition withinabout 45 min when tested in an in vitro dissolution test according toUSP dissolution test (paddle) employing water as dissolution medium, 100rpm and a temperature of about 37° C.

In another embodiment about 50% w/w or more of the fibrate and/or thestatin is released from the composition within about 20 min, 15 min or10 min, and/or about 60% w/w or more of the fibrate and/or the statin isreleased from the composition within about 20 min or 15 min, and/orabout 70% w/w or more of the fibrate and/or the statin is released fromthe composition within about 20 min or 15 min, when tested in an invitro dissolution test according to USP dissolution test (paddle)employing water as dissolution medium, 100 rpm and a temperature ofabout 37° C.

In a still further embodiment about 50% w/w or more of the fibrateand/or the statin contained in the composition is absorbed within about8 hours, 7 hours, 6 hours or 5 hours, and/or about 60% w/w or more ofthe fibrate and/or statin contained in the composition is absorbedwithin about 8 hours or 7 hours after oral administration, and/or about60% w/w or more of the fibrate contained in the composition is absorbedwithin about 7 hours after oral administration, and/or about 70% w/w ormore of the fibrate contained in the composition is absorbed withinabout 8 hours or 7 hours after oral administration.

The details and particulars disclosed under this main aspect of theinvention apply mutatis mutandis to the other aspects of the invention.Accordingly, the properties with respect to increase in bioavailability,changes in bioavailability parameters, reduction in adverse food effectas well as release of one or more fibrates etc. described and/or claimedherein for pharmaceutical compositions in particulate form are analoguesfor a solid dosage form according to the present invention.

Materials and Methods Materials Fenofibrate (supplied by Sigma)Atorvastatin magnesium, atorvastatin calcium (supplied by Biocon)Simvastatin (supplied Biocon) Lactose monohydrate 200 mesh (from DMV)

Mannitol. Pearlitol 50 C (from Roquette, France)

Polyethylene glycol 6000, Pluracol® E6000 (from BASF) Poloxamer 188,Pluronic® F-68 (from BASF) Avicel PH200 (microcrystalline cellulose)(from FMC) Ac-di-sol (croscarmellose sodium, from FMC Corp., U.S.A.)Trometamol (from Dow France (Angus)) Klucel (from Hercules Inc, U.S.A.)Magnesium stearate

Tablets, capsules or granules may be enteric coated with different typesof polymers such as hydroxypropylmethylcellulose acetate succinate(Aqoat), cellulose acetate phthalate CAP, hydroxypropylmethylcellulosephtalate HPMCP or methacrylic acid copolymers such as Eudragit L30D,Eudragit 100/S, Eudragit 100/L.

Equipment

Laboratory scale fluid bed equipment: Strea-1.The melt feed unit is a prototype composed of separate units for heatingof air supplies for the atomizer, pressure tank and feeding tube.Granulate was sieved manually and mixed with extragranular excipients ina Turbula mixer.

Tablet compression was performed on a multilayer (bi-layer) tabletmachine. Methods

The fenofibrate drug may be dissolved into the melted vehicle(s) andapplied on the particulate carrier(s) as follows:

The vehicle(s) was melted in a beaker placed in a microwave oven. Thebeaker was transferred to a temperature controlled heating platesupplied with magnetic stirring. Fenofibrate was dissolved slowly in themelt at a temperature of 75° C. under magnetic stirring. The hotsolution was transferred to the pressure tank for melt spray applicationonto the carrier in the fluid bed. The granulate product was dischargedfrom the fluid bed and sieved through sieve 0.7 mm or 1.0 mm manually.The sieved product was blended with magnesium stearate for 0.5 min in aTurbula mixer. If an extragranular phase has to be incorporated, theextragranular phase was premixed with the granulate in 3 minutes in aTurbula mixer.

Release Test

A fat-soluble colorant Sudan II (BDH Gur®) obtained from BDH VWRInternational 14.3 mg was dissolved in 50.0 g viscoleo (fractionatedmedium chain triglycerides).

10 g of the oil was added to 10.0 g of the solid pharmaceuticallyacceptable material to be tested for use according to the presentinvention and mixed until the oil was fully absorbed in the solidmaterial. The mixture was subsequently sieved through sieve 0.3 mm toachieve a homogeneous mixture.

1.00 g of the mixture was transferred to a centrifugal tube and 3.00 mlof water was added. The suspension was mixed in a blood sample turnerfor 1 hour and subsequently centrifuged for 10 minutes at 5000 rpm. Theupper phase of oil and water was transferred carefully to a beaker andthe water was evaporated in an oven at 80° C. until constant weight. Theamount of oil released from the solid material was calculated on basisof the weight of the remaining after evaporation of the water phase.

Disintegration Test

The disintegration time was determined according to the method describedin to Ph. Eur.

Dissolution Test

The test was performed in accordance with Ph. Eur 2.9.3 using the paddleapparatus.

The quantification was performed using HPLC with UV-detection.

Medium: 900 ml water with 0.75% sodium lauryl sulfate (SLS) Rotationspeed: 50 rpm Temperature: 37° C. Sampling time: 10, 20, 30, 45 and 60minutes Acceptance criteria: >75% at 45 minutes (for the stabilitystudy)

Test for Impurities Sample Preparation for Simvastatin:

10 tablets were grounded and about 957 mg of grounded tablet materialwas placed in a 25 mL volumetric flask. 5 mL of water was added and themixture was ultrasonicated for 10 minutes. Acetonitrile was added up toa total volumen of 25 mL and the mixture was ultrasonicated for further10 minutes, followed by filtration (0.45 micrometer filter). Theresulting material was diluted ×25 for quantification.

Sample Preparation for Atorvastatin:

10 tablets were grounded and about 963 mg±10 mg of grounded tabletmaterial was placed in a 25 mL volumetric flask. 5 mL of water and 15 mlacetonitrile was added and the mixture was stirred on a magnetic stirrerfor 60 minutes. Acetonitrile was added up to a total volume of 25 mL andfiltrated through 0.45 μm filter. The sample is diluted ×25 forquantification. Both concentrated and diluted sample was injected intothe HPLC system HPLC:

The sample was subjected to HPLC analysis on a Shimadzu 2010A with autosampler cooling and dual wavelength UV detector.

Eluent A: 10.6 mM formic acid (in water). Eluent B: 10.6 mM formic acid(in acetonitrile). Column: varian Pursuit C18 3 micro, 150×3.0 mm

Oven temperature: 30° C.Injection volume: 15 microliter

Flow: 0.5 mL/min Gradient:

Time (min) Eluent A Eluent B 0.0 60 40 0.5 60 40 30.0 15 85 35.0 60 4040.0 60 40

Detection wavelength—fenofibrate: 295 nm Detectionwavelength—simvastatin/atorvastatin: 240 nm Determination of WeightVariation

The tablets prepared in the Examples herein were subject to a test forweight variation performed in accordance with Ph. Eur.

Determination of Average Tablet Hardness

The tablets prepared in the Examples herein were subject to at test fortablet hardness employing Schleuniger Model 6D apparatus and performedin accordance with the general instructions for the apparatus.

Determination of Solid Solution

According to the present invention, the fibrate is dissolved in avehicle. In order to substantiate this, a test involving differentialscanning calometry is performed. The test is performed on theparticulate composition, solid dosage form or mixture of vehicle andfibrate (after the solid solution is supposed to form). Standard DSCequipment connected to a PC is used.

Sample size: 10 mg in alu pansHeating rate: 5° C./min from 27° C. to 110° C.

Evaluation: The fibrate is considered to be in dissolved state ornon-crystalline if no fibrate endotherm peak is observed and if themelting interval does not significantly shift compared with the vehiclealone.

This invention may be embodied in other forms or carried out in otherways without departing from the spirit or essential characteristicsthereof. The present disclosure is therefore to be considered as in allaspects illustrate and not restrictive, and all changes which comewithin the meaning and range of equivalency are intended to be embracedtherein.

EXAMPLE 1 Preparation of Fenofibrate Granulate

The following fenofibrate granulate denoted 1A was prepared as describedabove under Methods and in WO-A-2005/034920, which is incorporated byreference in its entirety. ‘mg/tablet’ denotes the amounts present inthe pharmaceutical composition of the invention in a single solid dosageform (a tablet):

1A Substance Ingredients % mg/tablet Drug Fenofibrate 19.6 160.00Carrier Lactose 43.6 356.50 Vehicle PEG 6000 25.4 208.20 VehiclePoloxamer 188 10.9 89.20 Excipient Magnesium stearate 0.5 4.10 100.0818.00

The following fenofibrate granulates denoted 1B, 1C, 1D and 1E wereprepared as described above under Methods and in WO-A-2005/034920, whichis incorporated by reference in its entirety. ‘mg/tablet’ denotes theamounts present in the pharmaceutical composition of the invention in asingle solid dosage form (a tablet):

Sub- 1B 1C 1D 1E 1F 1G 1H stance Ingredient mg mg mg mg mg mg mg DrugFenofibrate 130 43 48 145 120 110 100 Vehicle PEG6000 169 56 62 189 157144 131 1 Vehicle Poloxamer 72 24 27 81 67 61 56 2 188 Carrier Lactose304 101 112 339 282 258 235 Excip- Mg 1.3 0.5 2.5 7.6 6.3 5.8 5.3 ientsstearate

EXAMPLE 2 Preparation of Simvastatin Granulate

The following simvastatin granulate denoted 2A was prepared using aconventional wet granulation method.

‘mg/tablet’ denotes the amounts present in the pharmaceuticalcomposition of the invention in a single solid dosage form (a tablet):

Substance Ingredient % mg/tablet Drug Simvastatin 4.9 10.0 CarrierLactose 350 mesh 33.0 68.0 Excipients Magnesium stearate 0.5 1.0 Talc0.2 0.4 Starch 1500 9.8 20.0 Klucel (hydroxy propyl cellulose) 1.5 3.0Citric acid/BHA (antioxidant) 1.1 2.5 Avicel PH200 (microcryst.cellulose) 49.5 102.0

EXAMPLE 3 Preparation of Atorvastatin Granulate

The following atorvastatin granulate denoted 3A was prepared in aconventional manner using wet granulation, i.e. mixing atorvastatin,lactose (carrier) and calcium carbonate (stabilizer), adding theappropriate amount of hydroxypropyl cellulose (Klucel; binder) andnatrium carboxymethyl cellulose (Ac-di-sol; disintegrant), addingsterile water to the mixture, mixing and drying off the water, siftingthe dried mixture and adding magnesium stearate (lubricant) andmicrocrystalline cellulose (Avicel).

The following atorvastatin granulate denoted 3B was prepared in aconventional manner using wet granulation: A binder solution is preparedby dissolving hydroxypropyl cellulose (binder) and trometamol(stabilizer) in water (surfactant may be added, e.g. Polysorbat 80).Atorvastatin, mannitol (carrier), hydroxypropyl cellulose (binder) andmicrocrystalline cellulose (Avicel; filler) is transferred to a highshear mixer. The dry ingredients are premixed for 2 minutes, followed byaddition of the binder solution at 150 rpm (impeller) and 2000 rpm(chopper) to form a wet mass. Water is added and the mixture is mixedfor 2 minutes, resulting in granule formation. The wet granulate issieved (1.0 mm round opening) and dried in a fluid bed. The drygranulate is sieved (1.0 mm round opening). ‘%’ denotes percentage ofgranulate.

‘mg/tablet’ denotes the amounts present in the pharmaceuticalcomposition of the invention in a single solid dosage form (a tablet):

3A 3B Substance Ingredient % mg/tablet % mg/tablet Drug Atorvastatin 5.310.9 14.6 44 magnesium Carrier Lactose 200 mesh 16.1 32.8 — — Mannitol —— 41 122 (Pearlitol 50C) Excipients Magnesium stearate 0.5 1.00 0.5 1.5Ac-di-sol 5.0 10.2 — — Calcium carbonate 16.2 33.0 — — Klucel 1.5 3.02.4 7 Polysorbate 80 0.4 0.6 0.8 2.4 Avicel 55.0 111.7 40 119 Trometamol— — 0.8 2.5

EXAMPLE 4 Tablet of the Invention—Atorvastatin

A two-layer tablet denoted 4E was prepared in a conventional manner in atableting machine (manufactured by Fette GmbH, Germany) usingfenofibrate granulate 1E of example 1 and atorvastatin granulate 3B ofexample 3, the resulting tablet having a weight of about 1060 mg.

A two-layer tablet denoted 4B was prepared in a conventional manner in atableting machine (manufactured by Fette GmbH, Germany) usingfenofibrate granulate 1F of example 1 and atorvastatin granulate 3B ofexample 3, the resulting tablet having a weight of about 930 mg.

EXAMPLE 5 Tablet of the Invention—Simvastatin

A two-layer tablet denoted 5E was prepared in a conventional manner in atableting machine (manufactured by Fette GmbH, Germany) usingfenofibrate granulate 1E of example 1 and simvastatin granulate 2A ofexample 2, the resulting tablet having a weight of about 938 mg.

A two-layer tablet denoted 5B was prepared in a conventional manner in atableting machine (manufactured by Fette GmbH, Germany) usingfenofibrate granulate 1B of example 1 and simvastatin granulate 2A ofexample 2, the resulting tablet having a weight of about 853 mg.

EXAMPLE 6 Comparison Example—Stability of Pharmaceutical Composition ofthe Invention (Simvastatin)

It is known that simvastatin may degrade to the corresponding hydroxyacid upon storage, thus creating ‘impurities’ in the pharmaceuticalcomposition comprising simvastatin.

Stability of the fixed dose fenofibrate and simvastatin tablets preparedaccording to the invention (example 5) was measured as described above(test for impurities) after 1 month storage at 25° C. and 60% RH. Thecomparison tablet was a tablet prepared by mixing the fenofibrategranulate 1E (example 1) and the simvastatin granulate 2A (example 2)and compressing the combined granulate into a tablet.

Results:

Hydroxy acid Formulation % of simvastatin Index Comparison (granulatemix) 3.9 1857 Tablet with pharmaceutical 0.2 100 composition of theinvention

The result clearly demonstrates that a single solid dosage form preparedaccording to the invention (a two-layer tablet in this embodiment) issignificantly more stable than a tablet prepared from a simple mix ofsimilar active substance granulates.

EXAMPLE 7 Stability of Pharmaceutical Composition of the Invention(Atorvastatin)

Stability of the fixed dose fenofibrate and atorvastatin tabletsprepared according to the invention (example 4) was measured asdescribed above (test for presence of atorvastatin in lactone form,varying amounts of trometamol stabilizer) after 1 month storage at 40°C. and 75% RH.

Results:

Trometanole added 1% w/w 2% w/w 5% w/w Lactone content <0.05% <0.05%<0.05%

1. A composition for oral administration comprising a fixed dosecombination of a first solid composition containing fenofibrate as theactive substance and second solid composition containing an HMG-CoAreductase inhibitor as the active substance, wherein the first and thesecond composition are present in separate entities in a single soliddosage form.
 2. The composition according to claim 1, wherein the firstsolid composition is in the form of granulate, granules, grains, beadsor pellets.
 3. The composition according to claim 1, wherein the secondsolid composition is in the form of granulate, granules, grains, beadsor pellets.
 4. The composition according to claim 3, wherein thegranules, granulate, grains, beads or pellets are entero-coated.
 5. Thecomposition according to claim 3, wherein the granules, granulate,grains, beads or pellets are coated with a protective coating.
 6. Thecomposition according to claim 1 in the form of a capsule or a sachet.7. The composition according to claim 1 in the form of a tablet.
 8. Thecomposition according to claim 7, wherein the first and secondcompositions are present in the tablet in separate layers.
 9. Thecomposition according to claim 8, wherein a layer comprising the firstcomposition is separated from a layer comprising the second compositionby an intermediate, inactive layer.
 10. The composition according toclaim 1, wherein the HMG-CoA reductase inhibitor is a statin selectedfrom the group consisting of atorvastatin, lovastatin, pravastatin,simvastatin, rosuvastatin, fluvastatin and pitavastatin.
 11. Thecomposition according to claim 10, wherein the HMG-CoA reductaseinhibitor is simvastatin.
 12. The composition according to claim 11comprising a fixed dose combination selected from the group consistingof simvastatin 5 mg and fenofibrate 100 mg; simvastatin 10 mg andfenofibrate 100 mg; simvastatin 20 mg and fenofibrate 100 mg;simvastatin 40 mg and fenofibrate 100 mg; simvastatin 80 mg andfenofibrate 100 mg; simvastatin 5 mg and fenofibrate 110 mg; simvastatin10 mg and fenofibrate 110 mg; simvastatin 20 mg and fenofibrate 110 mg;simvastatin 40 mg and fenofibrate 110 mg; simvastatin 80 mg andfenofibrate 110 mg; simvastatin 5 mg and fenofibrate 120 mg; simvastatin10 mg and fenofibrate 120 mg: simvastatin 20 mg and fenofibrate 120 mg;simvastatin 40 mg and fenofibrate 120 mg; and simvastatin 80 mg andfenofibrate 120 mg; simvastatin 5 mg and fenofibrate 130 mg; simvastatin10 mg and fenofibrate 130 mg simvastatin 20 mg and fenofibrate 130 mg;simvastatin 40 mg and fenofibrate 130 mg; simvastatin 80 mg andfenofibrate 130 mg; simvastatin 5 mg and fenofibrate 145 mg; simvastatin10 mg and fenofibrate 145 mg: simvastatin 20 mg and fenofibrate 145 mg;simvastatin 40 mg and fenofibrate 145 mg; and simvastatin 80 mg andfenofibrate 145 mg.
 13. The composition according to claim 10, whereinthe HMG-CoA reductase inhibitor is atorvastatin.
 14. The compositionaccording to claim 13, wherein the atorvastatin is selected from thegroup consisting of crystalline atorvastatin calcium, amorphousatorvastatin calcium, crystalline atorvastatin magnesium, amorphousatorvastatin magnesium, a mixture of amorphous and crystallineatorvastatin calcium and a mixture of amorphous and crystallineatorvastatin magnesium.
 15. The composition according to claim 13,wherein the atorvastatin is crystalline atorvastatin magnesium.
 16. Thecomposition according to claim 13 comprising a fixed dose combinationselected from the group consisting of atorvastatin 5 mg and fenofibrate100 mg; atorvastatin 10 mg and fenofibrate 100 mg; atorvastatin 20 mgand fenofibrate 100 mg; atorvastatin 40 mg and fenofibrate 100 mg;atorvastatin 80 mg and fenofibrate 100 mg; atorvastatin 5 mg andfenofibrate 110 mg; atorvastatin 10 mg and fenofibrate 110 mg;atorvastatin 20 mg and fenofibrate 110 mg; atorvastatin 40 mg andfenofibrate 110 mg; atorvastatin 80 mg and fenofibrate 110 mg;atorvastatin 5 mg and fenofibrate 120 mg; atorvastatin 10 mg andfenofibrate 120 mg: atorvastatin 20 mg and fenofibrate 120 mg;atorvastatin 40 mg and fenofibrate 120 mg; and atorvastatin 80 mg andfenofibrate 120 mg; atorvastatin 5 mg and fenofibrate 130 mg;atorvastatin 10 mg and fenofibrate 130 mg: atorvastatin 20 mg andfenofibrate 130 mg; atorvastatin 40 mg and fenofibrate 130 mg; andatorvastatin 80 mg and fenofibrate 130 mg; atorvastatin 5 mg andfenofibrate 145 mg; atorvastatin 10 mg and fenofibrate 145 mg:atorvastatin 20 mg and fenofibrate 145 mg; atorvastatin 40 mg andfenofibrate 145 mg; and atorvastatin 80 mg and fenofibrate 145 mg. 17.The composition according to claim 13 which further comprises astabilizer capable of providing a microenvironment for atorvastatinhaving a pH of at least about
 5. 18. The composition according to claim13 which further comprises a stabilizer capable of providing amicroenvironment for atorvastatin having a pH of at least about
 6. 19.The composition according to claim 13 which further comprises astabilizer selected from the group consisting of inorganic alkalizingcompounds.
 20. The composition according to claim 19, wherein thestabilizer is selected from the group consisting of metal salts,alkaline earth metal salts, talc and bentonite.
 21. The compositionaccording to claim 19, wherein the stabilizer is selected from the groupconsisting of calcium salts (calcium carbonate, calcium hydroxide, dicalcium phosphate, tri calcium phosphate), magnesium salts (magnesiumcarbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate,aluminum magnesium hydroxide), lithium salts (lithium hydroxide),potassium salts (potassium hydroxide) and sodium salts (sodiumbicarbonate, sodium borate, sodium carbonate, sodium hydroxide).
 22. Thecomposition according to claim 13 which further comprises a stabilizerselected from the group consisting of organic alkalizing compounds. 23.The composition according to claim 22, wherein the stabilizer isselected from the group consisting of amines, amides and ammoniumcompounds.
 24. The composition according to claim 22, wherein thestabilizer is selected from the group consisting of ammonia, ammoniumlactate, ammonium bicarbonate, ammonium hydroxide, ammonium phosphatedibasic, mono ethanolamine, di ethanolamine, tri ethanolamine, trihydroxymethylaminomethane, ethylenediamine, N-methyl glucamide,6N-methyl glucamine, meglucamine, L-lysine and2-amino-2-(hydroxymethyl)-1,3-propanediol.
 25. The composition accordingto claim 17, wherein the stabilizer is2-amino-2-(hydroxymethyl)-1,3-propanediol.
 26. The composition accordingto claim 1, wherein the second composition comprises atorvastatin andfrom about 0.01% w/w to about 5% w/w of2-amino-2-(hydroxymethyl)-1,3-propanediol.
 27. The composition accordingto claim 1, wherein the first or the second composition furthercomprises acceptable excipients.
 28. The composition according to claim1, wherein the first composition comprises micronized crystallinefenofibrate.
 29. The composition according to claim 1, wherein the firstcomposition comprises a solid solution of fenofibrate dissolved in avehicle comprising polyethylene glycol (PEG).
 30. The compositionaccording to claim 27, wherein the first composition comprises a solidsolution of fenofibrate dissolved in a vehicle comprising polyethyleneglycol 6000 (PEG 6000) and poloxamer
 188. 31. The composition accordingto claim 27, wherein the first composition comprises lactose as acarrier.
 32. The composition according to claim 27, wherein the firstcomposition comprises magnesium stearate as a lubricant.
 33. Thecomposition according to claim 1, wherein the second compositioncomprises simvastatin and lactose as a carrier.
 34. The compositionaccording to claim 1, wherein the second composition comprisesatorvastatin magnesium and mannitol as a carrier.
 35. The compositionaccording to claim 27, wherein the second composition comprisesmagnesium stearate as a lubricant.
 36. The composition according toclaim 27, wherein the second composition comprises starch as adisintegrant.
 37. The composition according to claim 27, wherein thesecond composition comprises one or more antioxidants selected from thegroup consisting of ascorbic acid, citric acid and butyl hydroxylanisole.
 38. The composition according to claim 27, wherein the secondcomposition comprises microcrystalline cellulose as a filler.
 39. Thecomposition according to claim 1, wherein the single solid dosage formis a two-layer tablet prepared by compressing the first composition inthe form of granulate together with the second composition in the formof granulate
 40. The composition according to claim 1, wherein thesingle solid dosage form is a two-layer tablet prepared by compressingthe first composition in the form of granulate together with the secondcomposition in the form of granulate having a protective coating. 41.The composition according to claim 1, wherein the single solid dosageform is a two-layer tablet prepared by compressing the first compositionin the form of granulate together with the second composition in theform of entero-coated granulate.
 42. The composition according to claim1 containing not more than 0.5% atorvastatin in lactone form afterstorage at 40° C. and 75% relative humidity for 1 month.
 43. Thecomposition according to claim 1 containing not more than 0.1%atorvastatin in lactone form after storage at 40° C. and 75% relativehumidity for 1 month.
 44. The composition according to claim 1containing not more than 0.05% atorvastatin in lactone form afterstorage at 40° C. and 75% relative humidity for 1 month.
 45. Thecomposition according to claim 1 for the treatment of a subjectsuffering from atherosclerosis, hyperlipidemia, and/orhypercholesterolemia.
 46. The composition according to claim 43 for thetreatment of a human subject.
 47. A method for preparing a tabletcomprising a first solid composition containing fenofibrate as theactive substance and second solid composition containing an HMG-CoAreductase inhibitor as the active substance, the first and the secondcomposition being present in separate entities, which method comprisesthe steps of: i) preparing the first solid composition by dissolvingfenofibrate in a vehicle and spraying the resulting liquid solution on asolid carrier in a controlled agglomeration process, optionally mixingthe agglomerated particles with a lubricant, and mixing the agglomeratedparticles to form a granulate, ii) preparing the second solidcomposition by wet granulation, and iii) compressing the first andsecond compositions into a multilayer tablet, the first and secondcompositions being present in separate layers.
 48. A single solid dosageform comprising a composition for oral administration comprising a fixeddose combination of a first solid composition containing fenofibrate asthe active substance and second solid composition containing an HMG-CoAreductase inhibitor as the active substance, wherein the first and thesecond composition are present in separate entities.